AB0022 SELECTIVE ESTROGEN RECEPTOR MODULATORS AND TISSUE-SELECTIVE ESTROGEN COMPLEX DO NOT SHARE ESTROGENIC EFFECTS ON IGG SIALYLATION IN AUTOIMMUNE CONDITIONS
Authors: P. Gupta, K. L. Gustafsson, H. Carlsten, P. Henning, C. Engdahl
Journal: Annals of the Rheumatic Diseases (2022)

Background Women entering menopause, with a decrease in estrogen levels, display an increased incidence of rheumatoid arthritis (RA). Estrogen (E2) treatment has beneficial effects on IgG pathogenicity by altering the sialylation grade which affect the binding ability to FcR 1 . E2 replacement may therefore be beneficial in pre-RA patients having autoantibodies. Exposure to estrogen is associated with negative side effects, therefore selective estrogen receptor modulators (SERMs) have been developed with estrogenic protective effect on bone but minimal impact on the reproductive system 2 . The SERM, Bazeodoxifene (BZA), as well as tissue-selective estrogen complex (TSEC), a combination of conjugated estrogen and BZA, have been approved for treatment of postmenopausal bone loss 3-5 Objectives The purpose of this study was to investigate the impact of BZA and TSEC on IgG sialylation grade which affects the pathogenicity as well as to determine the effects on total serum protein sialylation. Methods C57Bl6 mice were subjected to ovariectomy to stop the endogenous E2 production and mimicked the postmenopausal status. Mice were then treated with E2, BZA, TSEC, or vehicle, followed by ovalbumin (OVA) immunization to induce the IgG levels. Blood was collected before treatment started and at termination. In serum total IgG, OVA specific IgG and the degree of IgG-sialylation were quantified with ELISA. Sialyation of total serum proteins was determined with sialic acid assay quantification kit. Expression of sialyltransferase protein was analyzed in the bone marrow (BM) and spleen cell compartment using flow cytometry. The mRNA expression of glycosyltransferase was analyzed by qPCR analysis. Results Neither BZA nor TSEC significantly altered the total IgG levels or sialylation grade of IgG. Indeed, E2 significantly altered IgG sialylation. We showed that BZA increased sialyltransferase protein in plasma cells in a similar manner as E2. Further, neither E2, BZA or TSEC had any significant impact on sialic acids in whole serum protein and not in the mRNA expression of glycosyltransferase in the liver, BM, or gonadal fat. Conclusion In this study, we were not able to detect any alteration by TSEC or BZA treatment on IgG-sialylation grade and thereby pathogenicity of the IgG. Neither E2 nor BAZ or TSEC show any significant alteration on general sialylation, but our results suggest that further studies are required to understand E2, SERM, and TSEC full effect on protein sialylation in autoimmune conditions. Keywords: IgG sialylation, protein glycosylation, SERMs References [1]Engdahl C, Bondt A, Harre U, et al. Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Research &amp; Therapy . 2018/05/02 2018;20(1):84. doi:10.1186/s13075-018-1586-z [2]Pinkerton JV, Thomas S. Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol . Jul 2014;142:142-54. doi:10.1016/j.jsbmb.2013.12.011 [3]Miller PD, Chines AA, Christiansen C, et al. Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res . Apr 2008;23(4):525-35. doi:10.1359/jbmr.071206 [4]Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric . Oct 2012;15(5):411-8. doi:10.3109/13697137.2012.696289 [5]Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res . Dec 2008;23(12):1923-34. doi:10.1359/jbmr.080710 Disclosure of Interests None declared